The role of somatic mutational events in the pathogenesis of epilepsy

Abstract

Purpose of review: There has been rapid progress in defining novel causative gene variants responsible for a large spectrum of human epilepsy syndromes and subtypes. Of particular interest is the discovery that somatic mutations, for example, noninherited mutations occurring in neuroglial progenitor cells during embryonic brain development, are highly linked to malformations of cortical development (MCD) such as focal cortical dysplasia (FCD) type II and hemimegalencephaly.

Recent findings: Somatic gene variants have been identified in genes encoding regulatory proteins within the mechanistic target of rapamycin (mTOR) signaling cascade and have thus comprised the group classified as mTORopathies. FCD II and hemimegalencephaly often result from mutations in identical genes suggesting that these are spectrum disorders. An exciting recent development has been the identification of somatic mutations causing both FCD Ia and nonlesional neocortical epilepsy.

Summary: Defining somatic gene mutations in brain tissue specimens has shed new light on how MCD form and the mechanisms of epileptogenesis associated with MCD. Trials of mTOR inhibitors in tuberous sclerosis complex have demonstrated that inhibition of mTOR activation in mTORopathies can reduce seizure frequency. New somatic mutations found for a variety of epilepsy syndromes may provide new targets for clinical therapeutics.

Figure 1.

Experimental strategy to identify somatic gene mutations in epilepsy. The ictal onset zone (depicted in red), often an MCD visualized via pre-operative MRI, is defined by EEG (grid, depth or stereo-EEG) electrodes. Genomic DNA is extracted from the resected tissue and from a blood sample. Next-generation sequencing approaches are implemented to define variants within known and novel genes.

Figure 2.

Effects of somatic mutations in epilepsy. In panel (a), a NeuN labeled brain section demonstrates cortical neurons and normal histopathology (modified from [34]). The red triangles represent neurons carrying somatic mutations scattered within the samples. Implicit in the somatic mechanism is that only a portion of cells carry the mutation and these are adjacent to cells with no genomic variants identified, thus representing a mosaic of affected and unaffected cells. (b) The developmental mechanism of somatic mutations begins with a mutation (red circle) in a mitotic progenitor cell within the VZ. The cell gives rise to daughter progeny also carrying the mutation which migrate to the cortex (red triangles as in (a)). The effects on cortical structure and network excitability may be cell autonomous i.e., from the mutation itself, (b) may reflect differential effects on different types of progenitors causing distinct cell types in MCD such as balloon cells (red ovoid shapes) in FCDII, or (c) may have non-cell autonomous effects on surrounding cells through changes in release of growth factors or neurotransmitters (red haze around circles).

Figure 3.

Possible functional links to epileptogenesis. There are 3 mechanisms that somatic mutations could cause seizures. The onset zone (b-d) is adjacent to normal cortex (a). The effects of variants can be purely “molecular” and causing intrinsic changes in excitability as in SLC35A2; (b), they may be a combination of “molecular” effects plus “structural” effects causing an MCD as in mTORopathies, or (c) the effects may include “molecular”, “structural”, and “network” alterations through aberrant connections to surrounding cortex (e).